It is believed that many human common diseases result from the complex interplay of genetic and environmental factors, and individual gene contributions are usually small and can be masked by genetic and environmental variations, posing a great challenge in studying genetic interactions in human diseases. Although animal models are indispensable and powerful tools for studying these interactions, current animal models are not suitable to study genetic interactions. Techniques must be developed to rapidly, specifically and sensitively study the interplay of genetic factors in any laboratory animal models over a wide genetic background, essential to understand and treat most human diseases.
The genome-wide association studies (GWAS) show that many common diseases result from the complex interplay of many genes and environmental factors, and that individual gene contributions are small and can be masked by genetic and environmental variations [1]. The history of mouse genetics also makes it clear that the genetic background can cause considerable phenotypic variation in the mice with the same targeted gene. These variables pose a great challenge in studying human disease gene-gene interactions. GWAS have failed to establish common variant risk for the majority of common diseases [15,20]. Animal models are indispensable and powerful tools that have tremendously increased knowledge of gene function. However, animal techniques that can sensitively study gene-gene interactions over a wide genetic background required to decode complex human diseases have yet to be developed.
Current animal models are dependent on establishing a congenic strain and the presumption that animals within the strain are identical [6,7]. Unfortunately, these animals are still subject to genetic, epigenetic and environmental variations which can result in high background noise, low sensitivity, or even false data. Moreover, the lab mice have limited genetic diversity to recapitulate gene-gene interactions in human diseases.
Furthermore, most gene studies have focused on one gene and one strain. To recapitulate human disease gene-gene interactions, the targeted gene should be studied in a variety of inbred strains and wild mice to find interactors of the gene. However, the outbreeding will lose homogeneity, making it virtually impossible to study the gene, and a “congenic” strain from backcrossing has variations as stated above.